Our long-term goal is to enhance our understanding of metalloprotein structure, function and inhibition. The tools we will use are those of theoretical, computational and medicinal chemistry. The long-term goal of the present proposal is to use these techniques to understand the structure, function and inhibition of the family of zinc (and magnesium) dependent sulfur alkylation enzymes called protein prenyltransferases. In particular, we will be study farnesyltransferase (FTase) and geranylgeranyltransferase type I (GGTase) using quantum mechanical (QM), QM/molecular mechanical (MM), molecular dynamics simulations, QM based X- ray refinement and docking/scoring studies. The overarching biological question we are addressing is the catalytic mechanism of zinc catalyzed protein prenylation and how this process can be inhibited to generate compounds relevant to cancer treatment, as well as other diseases. To reach this important biological goal we propose to study small molecule/enzyme interactions and the mechanism of these zinc catalyzed enzyme reactions using our theoretical tools. In order to enhance the quality of our computational efforts we are collaborating with experimentalists who are expert in the structure, function and inhibition of FTase and GGTase. Our experimental collaborators will assist in QM/MM based X-ray refinement studies, will generate mutant enzymes based on our computational observation in order to test our models, will carry out binding assays on novel small molecule inhibitors we identify and purchase and will synthesize novel compounds we propose. With the successful completion of the proposed project we will have generated mechanistic insights that will be translated into the design of novel inhibitors of FTase and GGTase that can be tested as treatment for human cancer.